The original Sign of the Cross was likely a "mini-cross" made by tracing a cross on the forehead, lips, or breast with the thumb, much like the custom today of doing so before the Gospel is read. It is difficult to determine exactly when the current custom of blessing oneself with a large cross going forehead to breast and then from shoulder to shoulder came about. Historical records in this regard are open to multiple interpretations and Church historians have divergent views on the subject. That the written record is unclear on the subject is to be expected, since such a custom would more likely be taught by example than by written instruction. It is likely that this large cross was first used in formal blessings by the clergy starting sometime during the Arian controversy of the fourth century and then eventually adopted by the laity. Clearly written instructions for using the large cross form to bless oneself appear by the 12/13th century, by which time it is also clear that the custom had been in use in some form or another for a long time, possibly since the 8th century.

As noted by various Medieval authors, this large Sign of the Cross is rich in symbolism. When Christ came to redeem the world, He descended from the Father, was born of the Virgin Mary, died, was buried, and descended to the dead. He then rose from the dead and ascended into heaven where He sits at the right hand of the Father. Thus when making the Sign of the Cross, one uses the right hand, which symbolizes Christ who sits at the right hand of the Father. Starting at the forehead, which symbolizes the Father, the Creator and source of all things, one then descends to the lower chest. This symbolizes the Incarnation, for Christ came down from heaven from the Father and became flesh in the womb of the Virgin Mary through the power of the Holy Spirit.

In the West, one then proceeds from the left shoulder to the right shoulder to finish the Sign of the Cross. The left in this case is usually associated with death and darkness, while the right symbolizes truth and light. Thus the action represents the transition from misery to glory, from death to life, and from hell to paradise. As Christ passed from death to life and sits at the right hand of the Father (left to right), so too may we pass from death to life in Christ through the sanctification of the Holy Spirit. In Eastern Christian traditions, the opposite direction is taken. One proceeds from the right to the left, so the symbolism is somewhat different.

A partial indulgence is granted to the faithful who devoutly make a sign of the cross.

"Go, therefore, and make disciples of all nations, baptizing them in the name of the Father, and of the Son, and of the Holy Spirit." (Matt. 28:19)